tbuckley/cabot-search huggingface dataset:
Trial designs and endpoints for immune therapies in multiple myeloma
Authors: Guido Lancman, Erin Moshier, Hearn Jay Cho, Samir Parekh, Shambavi Richard, Joshua Richter, Cesar Rodriguez, Adriana Rossi, Larysa Sanchez, Sundar Jagannath, Ajai Chari
Journal: American Journal of Hematology (2022)

Immune therapies, including CAR-T cells, bispecific antibodies, and antibody-drug conjugates, are revolutionizing the treatment of multiple myeloma. In this review, we discuss clinical trial design considerations relevant to immune therapies. We first examine issues pertinent to specific populations, including elderly, patients with renal impairment, high-risk/extramedullary disease, and prior immune therapies. We then highlight trial designs to optimize the selection of dose and schedule, explore rational combination therapies based on preclinical data, and evaluate the nuances of commonly used endpoints. By exploiting their pharmacokinetic/pharmacodynamic profiles and utilizing novel translational insights, we can optimize the use of immune therapies in multiple myeloma.
The COVID-19 pandemic and pulmonary arterial hypertension in Italy: adaptation, outcomes and valuable lessons learned
Authors: Claudia Mickael, Michael H. Lee, Brian B. Graham
Journal: European Respiratory Journal (2022)

<b>This editorial summarises the key findings of R. Badagliacca and co-workers regarding the changes in care and clinical outcomes of PAH patients during the initial COVID-19 pandemic in Italy</b>https://bit.ly/3ytgIjk
Progressive pulmonary fibrosis: all roads lead to Rome (but not all at the same speed)
Authors: Vincent Cottin, Claudia Valenzuela
Journal: European Respiratory Journal (2022)

<b>Large observational cohorts show that eventually, a majority of patients with fibrotic ILD will experience disease progression. Highest rates of progression are seen in patients with idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis.</b> https://bit.ly/3QcnVKJ
The lower respiratory tract: the hot spot for chronic fixed airflow limitation
Authors: Francesca Polverino, Jose M. Marin
Journal: European Respiratory Journal (2022)

Persistent airflow limitation in children and young adults is emerging as an umbrella term encompassing various biological and clinical manifestations occurring during the lifespan and starting before birth [1, 2]. The previous model of an accelerated decline of lung function, that would become manifest in adult life in susceptible individuals when chronically exposed to environmental noxious agents, such as cigarette smoke and other inhaled gases, has made way for a more comprehensive model where events occurring during the first years of life are key in predicting the trend of one's lung function during the lifespan [3–6]. Asthma and lower respiratory tract infections (LRIs) are major factors determining low lung function early in life, can persist into young adulthood and become fixed airflow limitation [7, 8]. However, to which extent, and what kind of, respiratory infections in early life are associated with the risk of wheezing or asthma in later life remains unknown. The small airways are key for the childhood events that shape into chronic fixed airflow limitation later in life <https://bit.ly/3OOBdeW>
PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing
Authors: Yiting Jia, Chenfeng Mao, Zihan Ma, Jiaqi Huang, Wenqiang Li, Xiaolong Ma, Siting Zhang, Meihong Li, Fang Yu, Yingying Sun, Jingzhou Chen, Juan Feng, Yuan Zhou, Qingbo Xu, Ling Zhao, Yi Fu, Wei Kong
Journal: Circulation Research (2022)

Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis of a variety of vascular diseases during the early stage. Recent studies indicate the metabolic reprogramming may be involved in VSMC phenotypic transition. However, the definite molecules that link energy metabolism to distinct VSMC phenotype remain elusive.A carotid artery injury model was used to study postinjury neointima formation as well as VSMC phenotypic transition in vivo. RNA-seq analysis, cell migration assay, collagen gel contraction assay, wire myography assay, immunoblotting, protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay were performed to clarify the phenotype and elucidate the molecular mechanisms.We collected cell energy-regulating genes by using Gene Ontology annotation and applied RNA-Seq analysis of transforming growth factor-β or platelet-derived growth factor BB stimulated VSMCs. Six candidate genes were overlapped from energy metabolism-related genes and genes reciprocally upregulated by transforming growth factor-β and downregulated by platelet-derived growth factor BB. Among them, prohibitin 2 has been reported to regulate mitochondrial oxidative phosphorylation. Indeed, prohibitin 2-deficient VSMCs lost the contractile phenotype as evidenced by reduced contractile proteins. Consistently, Phb2SMCKO mice were more susceptible to postinjury VSMC proliferation and neointima formation compared with Phb2flox/flox mice. Further protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay revealed that prohibitin 2, through its C-terminus, directly interacts with hnRNPA1, a key modulator of pyruvate kinase M1/2 (PKM) mRNA splicing that promotes PKM2 expression and glycolysis. Prohibitin 2 deficiency facilitated PKM1/2 mRNA splicing and reversion from PKM1 to PKM2, and enhanced glycolysis in VSMCs. Blocking prohibitin 2-hnRNPA1 interaction resulted in increased PKM2 expression, enhanced glycolysis, repressed contractile marker genes expression in VSMCs, as well as aggravated postinjury neointima formation in vivo.Prohibitin 2 maintains VSMC contractile phenotype by interacting with hnRNPA1 to counteract hnRNPA1-mediated PKM alternative splicing and glucose metabolic reprogramming.
Publisher Correction: The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET
Authors: Rosaria Talarico, Silvia Aguilera, Tobias Alexander, Zahir Amoura, Ana M. Antunes, Laurent Arnaud, Tadej Avcin, Lorenzo Beretta, Stefano Bombardieri, Gerd R. Burmester, Sara Cannizzo, Lorenzo Cavagna, Benjamin Chaigne, Alain Cornet, Nathalie Costedoat-Chalumeau, Andrea Doria, Alessandro Ferraris, Rebecca Fischer-Betz, João E. Fonseca, Charissa Frank, Andrea Gaglioti, Ilaria Galetti, Jürgen Grunert, Vera Guimarães, Eric Hachulla, Frederic Houssiau, Luca Iaccarino, Thomas Krieg, Marteen Limper, Fransiska Malfait, Xavier Mariette, Diana Marinello, Thierry Martin, Lisa Matthews, Marco Matucci-Cerinic, Alain Meyer, Carlomaurizio Montecucco, Luc Mouthon, Ulf Müller-Ladner, Simona Rednic, Vasco C. Romão, Matthias Schneider, Vanessa Smith, Alberto Sulli, Farah Tamirou, Domenica Taruscio, Anna V. Taulaigo, Enrique Terol, Angela Tincani, Simone Ticciati, Giuseppe Turchetti, P. Martin van Hagen, Jacob M. van Laar, Ana Vieira, Jeska K. de Vries-Bouwstra, Maurizio Cutolo, Marta Mosca
Journal: Nature Reviews Rheumatology (2022)
Association of the COVID-19 Pandemic With Prehospital Characteristics and Outcomes of Pediatric Patients With Out-of-Hospital Cardiac Arrest in Japan, 2005-2020
Authors: Ling Zha, Sanae Hosomi, Kosuke Kiyohara, Tomotaka Sobue, Tetsuhisa Kitamura
Journal: JAMA Network Open (2022)

This cohort study investigates the association of the COVID-19 pandemic with prehospital characteristics and outcomes of pediatric patients with out-of-hospital-cardiac arrest in Japan.
Use of the Postacute Sequelae of COVID-19 Diagnosis Code in Routine Clinical Practice in the US
Authors: Leah J. McGrath, Amie M. Scott, Andy Surinach, Richard Chambers, Michael Benigno, Deepa Malhotra
Journal: JAMA Network Open (2022)

Importance A new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code (U09.9 Post COVID-19 condition, unspecified) was introduced by the Centers for Disease Control and Prevention on October 1, 2021. Objective To examine the use of the U09.9 code and describe concurrently diagnosed conditions to understand physician use of this code in clinical practice. Design, Setting, and Participants This cohort study of US patients with an ICD-10-CM code for post–COVID-19 condition used deidentified patient-level claims data aggregated by HealthVerity. Children and adolescents (aged 0-17 years) and adults (aged 18-64 and ≥65 years) with a post–COVID-19 condition code were identified between October 1, 2021, and January 31, 2022. To identify a prior COVID-19 diagnosis, 3 months of continuous enrollment (CE) before the post–COVID-19 diagnosis date was required. Main Outcomes and Measures Presence of the ICD-10-CM U09.9 code. Results There were 56 143 patients (7723 female patients [61.2%]; mean [SD] age, 47.6 [19.2] years) with a post–COVID-19 diagnosis code, with cases increasing in mid-December 2021 following the trajectory of the Omicron case wave by 3 to 4 weeks. The analysis cohort included 12 622 patients after the 3-month preindex CE criteria was applied. Among this cohort, the median (IQR) age was 49 (35-61) years; however, 1080 (8.6%) were pediatric patients. The U09.9 code was used most often in the outpatient setting, although 305 older adults (14.0%) were inpatients. Only 698 patients (5.5%) had at least 1 of the 5 codes listed as possible concurrent conditions in the coding guidance. Only 8879 patients (70.4%) had a documented acute COVID-19 diagnosis code (569 [52.7%] among children), and the median (IQR) time between acute COVID-19 and post–COVID-19 diagnosis codes was 56 (21-200) days. The most common concurrently coded conditions varied by age; children experienced COVID-19–like symptoms (eg, 207 [19.2%] had cough and 115 [10.6%] had breathing abnormalities), while 459 older adults aged 65 years or older (21.1%) experienced respiratory failure and 189 (8.7%) experienced viral pneumonia. Conclusions and Relevance This retrospective cohort study found patients with a post–COVID-19 ICD-10-CM diagnosis code following the acute phase of COVID-19 disease among patients of all ages in clinical practice in the US. The use of the U09.9 code encompassed a wide range of conditions. It will be important to monitor how the use of this code changes as the pandemic continues to evolve.
Association of Visual Health With Depressive Symptoms and Brain Imaging Phenotypes Among Middle-Aged and Older Adults
Authors: Xiayin Zhang, Xianwen Shang, Ishith Seth, Yu Huang, Yaxin Wang, Yingying Liang, Zijing Du, Guanrong Wu, Yunyan Hu, Shunming Liu, Yijun Hu, Mingguang He, Zhuoting Zhu, Xiaohong Yang, Honghua Yu
Journal: JAMA Network Open (2022)

Importance Vision loss and depression are common conditions with major health implications. However, mechanisms of the association of visual health (across the full acuity spectrum) with depression remain unclear. Objective To characterize the association between visual health and depression and investigate the association between depression and brain microstructure and macrostructure in subgroups divided by visual acuity. Design, Setting, and Participants In the UK Biobank Study cohort, 114 583 volunteers were included at baseline from March to June 2006 to July 2010. Habitual distance visual acuity was examined using the logarithm of the minimum angle of resolution (LogMAR) characters. Depression was identified based on Patient Health Questionnaire (PHQ) or through an interview-based psychiatric diagnosis. Subgroup participants completed multimodal magnetic resonance imaging (MRI) of the brain and PHQ evaluation during the imaging visit after 2014. Data were analyzed from May 5 to August 9, 2022. Main Outcomes and Measures Depression, depressive symptoms, and imaging-derived phenotypes from T1-weighted and diffusion MRI. Results Of the 114 583 participants from the UK Biobank Study, 62 401 (54.5%) were women, and the mean (SD) age was 56.8 (8.1) years (range, 39-72 years). A 1-line worse visual acuity (0.1 LogMAR increase) was associated with 5% higher odds of depression (odds ratio, 1.05 [95% CI, 1.04-1.07]) after adjustment for age, sex, race and ethnicity, Townsend index, educational qualifications, smoking, alcohol consumption, obesity, physical activity, history of hypertension, diabetes, hyperlipidemia, and family history of depression. Of the 7844 participants eligible for MRI analysis, there were linear associations between PHQ score and the left volume of gray matter in supracalcarine cortex (coefficient, 7.61 [95% CI, 3.90-11.31]) and mean isotropic volume fraction (ISOVF) in the right fornix (cres) and/or stria terminalis (coefficient, 0.003 [95% CI, 0.001-0.004]) after correction for multiple comparison. In addition, their association could be moderated by visual acuity, whereby increased PHQ score was associated with higher ISOVF levels only among those with poorer visual acuity ( P = .02 for interaction). Conclusions and Relevance This study suggests an association between visual health and depression and that the diffusion characteristic of ISOVF in the fornix (cres) and/or stria terminalis is associated with depressive symptoms in participants with poorer visual acuity.
Errors in Abstract and Methods
Journal: JAMA Network Open (2022)

Armando Peña, PhD; Micah L. Olson, MD; Elva Hooker, RD, CDE; Stephanie L. Ayers, PhD; Felipe González Castro, PhD; Donald L. Patrick, PhD, MSPH; Libby Corral, BS; Elvia Lish, RD, CDE; William C. Knowler, MD, DrPH; Gabriel Q. Shaibi, PhD
Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on <i>KRAS</i> and <i>MEK</i> Alteration Status
Authors: Jithma P. Abeykoon, Karen L. Rech, Jason R. Young, Aishwarya Ravindran, Gordon J. Ruan, Surendra Dasari, Diana M. Morlote, Rebecca L. King, Claire Rummage, Saurabh Zanwar, Aldo M. Acosta-Medina, W. Oliver Tobin, Mithun V. Shah, N. Nora Bennani, Robert Vassallo, Jay H. Ryu, Matthew J. Koster, Caroline J. Davidge-Pitts, Thomas E. Witzig, Gaurav Goyal, Ronald S. Go
Journal: JAMA Oncology (2022)

Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments.To study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD.This retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis.Main outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD.A total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs.In this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.
Recognizing Minimal Cutaneous Involvement or Systemic Symptoms in Monkeypox
Authors: Rachel Eisenstadt, Walter J. Liszewski, Cuong V. Nguyen
Journal: JAMA Dermatology (2022)

This case report describes 2 umbilicated and ulcerated, skin-colored papules on the genitals, as well as a honey-colored crusted papule on the face.
Abdominal Extrarenal Involvement in Erdheim-Chester Disease in a Cohort of 304 Patients
Authors: Benjamin Dray, Jean-François Emile, Fleur Cohen-Aubart, Zahir Amoura, Mathilde Wagner, Julien Haroche, Olivier Lucidarme
Journal: JAMA Oncology (2022)

This cohort study estimates the prevalence of nonretroperitoneal abdominal organ involvement in Erdheim-Chester disease in a large cohort of patients.
Association Between Polycystic Ovary Syndrome and Risk of Pancreatic Cancer
Authors: Noah C. Peeri, Marco V. Landicino, C. Amethyst Saldia, Robert C. Kurtz, Vineet S. Rolston, Mengmeng Du
Journal: JAMA Oncology (2022)

This case-control study sought to confirm the exploratory finding of an association between polycystic ovary syndrome and risk of pancreatic cancer.
Pooled Analysis of Meningioma Risk Following Treatment for Childhood Cancer
Authors: Diana R. Withrow, Harald Anderson, Gregory T. Armstrong, Michael Hawkins, Neige Journy, Joseph P. Neglia, Florent de Vathaire, Margaret A. Tucker, Peter D. Inskip, Alina V. Brenner, Marilyn A. Stovall, Ibrahima Diallo, Amy Berrington de Gonzalez, Lene H. S. Veiga
Journal: JAMA Oncology (2022)

Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy.To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk.This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022.Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses.The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy).The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose.These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.
Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
Authors: Vincent Marmouset, Justine Decroocq, Sylvain Garciaz, Gabriel Etienne, Amine Belhabri, Sarah Bertoli, Lauris Gastaud, Célestine Simand, Sylvain Chantepie, Madalina Uzunov, Alexis Genthon, Céline Berthon, Edmond Chiche, Pierre-Yves Dumas, Jacques Vargaftig, Géraldine Salmeron, Emilie Lemasle, Emmanuelle Tavernier, Jérémy Delage, Marion Loirat, Nadine Morineau, Félix Blanc-Durand, Patricia Pautier, Véronique Vergé, Nathalie Auger, Myrtille Thomas, Laetitia Stefani, Marion Lepelley, Thomas Boyer, Sylvain Thepot, Marie-Pierre Gourin, Pascal Bourquard, Matthieu Duchmann, Pierre-Marie Morice, Mauricette Michallet, Lionel Adès, Pierre Fenaux, Christian Récher, Hervé Dombret, Arnaud Pagès, Christophe Marzac, Alexandra Leary, Jean-Baptiste Micol
Journal: Clinical Cancer Research (2022)

To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi).In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort.From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS.In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
Invisibility of breathlessness in clinical consultations: a cross-sectional, national online survey
Authors: Slavica Kochovska, Sungwon Chang, Diana Ferreira, Vanessa N. Brunelli, Tim Luckett, Lucy Morgan, Miriam J. Johnson, Magnus Ekström, David C. Currow
Journal: European Respiratory Journal (2022)

<b>Breathlessness is invisible in patient–clinician consultations. Improving clinical history taking is critical to help identify more consistently the presence and impact of breathlessness, especially for people living long-term with this disabling symptom.</b>https://bit.ly/3fD1nVS